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Another way the Republic of South Africa is trying to reinvent itself is in the way it regulates and reimburses for medicines. “BE” means not only “Black Empowerment” (in the post-apartheid sense) but also “bioequivalence.”
I’ve just returned from the “New Developments in Drug Regulation” conference in Pretoria, and there was a lot of serious discussion as to how government regulators can do a better job in a uniquely South African situation.
Some memorable moments …
Tomas Salmonson (Chair of the EMA’s CHMP) told the audience that, while he is a strong believer in transparency, he is not in favor of patient representatives on decision panels. Such representation, he said, “would be like having an elected parliament and then additional members.” He also does not believe that these meetings (akin in many ways to an FDA advisory committee meeting) should be open to the public. I pointed out that having patient reps and open adcomm meetings was a crucial part of the FDA process. Salmonson commented, “I know.”
Transparency translates in different ways. Salmonson noted that one way the EMA promulgates transparency is through its EPARS (European Public Assessment Reports System). The European Medicines Agency publishes an EPAR for every medicine granted a central marketing authorization by the European Commission. EPARs are full scientific assessment reports of medicines authorized at a European Union level.
Salmonson also made the point that a transparent process behind benefit/risk allows consumers and healthcare providers to trust the regulator. FDA – attention must be paid.
Peter Bachmann, head of the Germany’s BfArM (Federal Institute for Drugs and Medical Devices) Coordination Group Unit, spoke to the EMA’s philosophy of being “united in diversity” (a theme that certainly resonated in Pretoria). He also discussed the EMA’s program of mutual recognition, detailing the agency’s methodology of “work-sharing” – a process of cross-national regulatory peer review that should be studied by FDA policy panjandrums for many reasons, not the least of which is quality control.
Ngokoana Khomo, Vice Chair of South Africa’s MCC (Medicines Control Council – the South African version of the FDA) honestly spoke of the tension between “the policy and the practice” of medicines regulation in South Africa. Unspoken was the obvious under-current of a third “p” – politics. And perhaps a fourth – “Potemkin Regulation.” She spoke of the MCC’s mission as “access, equity, efficiency, quality, and sustainability.” Dr. Khomo wisely said that “transparency takes away all suspicions.” But saying and doing is not always the same thing. She also spoke about the rational use of medicine. After all, you can’t spell Ngokoana without NGO.
Ekkehard Baader (Senior Director, Head of EU Regulatory Affairs at Teva) addressed the importance of (and distinctions between) consultation, communications, and cooperation.
Speaking of Teva – there was no discussion of generic drugs during the conference. Not a single mention of API sourcing and quality, not a word about excipients. Disturbing considering the venue and the reality.
BfArM’s Birka Lehmann (a member of PDCO, the EMA’s Paediatric Committee) spoke about issues surrounding informed consent for children (“What if the baby is crying?”) as well as the need for a Paediatric Investigation Plan (PIP) at end of phase 1. Clearly an area ripe for FDA harmonization conversations. Clearly the pediatric train is moving – but EMA and FDA should be on the same track.
At this point you may be wondering what any of this has to do with regulatory reform in the Republic of South Africa. That question was also on the minds of many in the audience who asked questions like, “how much does all of this cost?” and “how many people do you need?” and “how do you train staff?”
Day 2 began with a focus on biosimilars and the successes and failures of the EMA experience – as well as a nod to the work being done by the WHO.
The presentation by Chris Holloway (Group Director of Regulatory Affairs & Chief Scientific Officer at the ERA Consulting Group) was the first person to use the word “quality” – and “process.” He spoke about “balancing needs against expectations.” And it was a welcome addition to the conversation. A breath of real-world reality vs. regulatory theory.
Elwyn Griffiths (WHO) likened his organization’s attempts to develop criteria for biosimilars to the League of Nations – but in a good way.
Haile Selassie, call your office.
Max Wegner (VP, Head of Global Regulatory Affairs, General Medicine at Bayer AG) addressed the unintended consequences of the EMA’s PRAC (Pharmacovigilance Risk Assessment Committee), specifically the impact of public reports of adverse events that had yet to be investigated. I added that the FDA had similar issues with Early Safety Signal Communications and the resultant unintended (but not entirely unsurprising) over reaction by the media and the ensuing leap in non-adherence.
Finally, Marc Blockman of the host Medicines Control Council (MCC) spoke on the issues surrounding both the importance of and difficulties with pharmacoviginance in South Africa. Two of his comments stand out: “Pharmacovigilance is a public service” Bravo. And, “Yes, we have a yellow card – but the form is as much the problem as it is the process.” Sounds familiar.
The conference was, as Pierre Abélard might have put it, a “sic et non” experience. Lots of good advice – but not a lot of applicable next steps. What makes this all the more urgent is the South African position on medicines reimbursement and intellectual property – which shares many philosophical underpinnings with that other bastion of IP protection – India.
Just as there are issues relative to South Africa’s need for regulatory capacity building, so too is capacity building and investment important for the future of intellectual property issues. One frightening passage in South Africa’s proposal states, “The Draft Policy proposes adopting strict patenting rules to “exclude diagnostic, therapeutic and surgical methods from patentability, including new uses of known products, as is the case under the TRIPS Agreement.” Not a good start for a nation that wants to be the “s” added to BRICS.
Further, South African law currently provides no regulatory data protection and the Draft Policy does not include any. Moreover, it explicitly rejects the utility of “blanket data protection” for innovator data and emphasizes the importance of “access to knowledge.” Uh oh. And, of course, there’s a magic rain dance call for compulsory licensing.
The Draft Policy encourages the use of parallel importation to improve access to medicines. Been there. Done that. A clear and present risk to patients.
And these are only a few examples. It gets worse.
The policy disconnect is profound. In April, South Africa sent a sizable delegation to the mega BIO convention with the message that they were “open for business,” and aspires to be a player in global life sciences.
At the same time, local generics manufacturers and the usual suspect activists are whipping up frenzy over intellectual property issues. The same old song. And a dangerous one considering that Scientific American ranks South Africa in the bottom 20% of its life science/innovation index.
(PS/ Under the current regulatory regime, it takes the MCC between 3-5 years after EMA or FDA approval t bring innovative therapeutics to South African patients – the slowest among “advanced” MEA nations. What’s wrong with this picture?)
Rather than looking to emulate the EMA, perhaps South Africa should adopt a reference basket of maybe five to six countries. A good model is Singapore. Everyone’s favorite city-state reviews seven countries—USA, Canada, Australia, NZ, Japan, Switzerland and the EMA. If any two of the seven have approved, then approval is basically a formality.
Talk is cheap.
There is nothing like returning to a place that remains unchanged to find the ways in which you yourself have altered. – Nelson Mandela
At CMPI’s recent Capital Hill conference ,Personalized Medicine and Responsible Access to Pain Medication, Dr. Charles Inturrisi, professor of pharmacology at the Weill Cornell Medical College, laid down the gauntlet:
I want to make a distinction that really does make a difference. And this is the distinction between efficacy and effectiveness. We know that opioids can provide analgesia for some chronic pain patients. We don’t know what percentage but we know that some, and you’ve heard from them this morning, at least one of them. But we also know the treatment outcomes with opioids are variable and not predictable. And this is the take home message if you have to leave. At present, there are no well-validated means of identifying optimal candidates for effective long-term chronic opioid therapy. That’s the problem. That’s the gap in our knowledge. That’s the gap in our evidence base.
We need to learn who will experience good analgesic effectiveness at stable dosages with limited side effects and low risk of abuse. So the critical question there is are there phenotypic or endo-genotypic characteristics that we can associate with better or worse outcomes that will help us to predict which patients might benefit and so that the cost-benefit ratio will be favorable rather than unfavorable.
Now I’m going to talk about personalized medicine in general and in particular. This refers to this emerging concept approach that uses patient-related factors including the phenotype, that is what information you can observe about the patient and a lot of that information now is contained in the electronic medical record. Also genotypic information that you can gain by collecting a sample and it can be either a sample of blood, or in some cases even a sample of saliva and by going through and looking at snips of DNA and creating biomarkers that select optimum medication and dosage for individual patients. It’s been estimated, on average, that prescription drugs are effective for only about half of those who take them. And for some drugs like anticancer drugs and antidepressants, the so-called non-responder rate is even higher.
Personalized medicine can reduce the non-responder rate because you can focus in on individuals who are highly associated with being respondersand you can eliminate the trial and error inefficiencies that inflate healthcare cost.
An audio recording on Dr. Inturrisi’s full comments can be found here (at the 1:03 mark) and the panel discussion that followed here.
On Friday CMS issued its final decision on beta amyloid imaging. It’s similar to their draft decision in that they ignored the recommendations of the medical community that was calling for full coverage for the Appropriate Use Criteria (AUC) population and imposed Coverage with Evidence Development (CED). CMS will only pay for Alzheimer's imaging tests used in clinical research or to exclude Alzheimer's disease when diagnosing patients in narrow circumstances. There are some slight changes from the initial draft, but from a patient access perspective, we are in the same boat as we were previously, which is non-coverage.
The Alzheimer's Association noted that, in the past, it has taken as long as seven years for CMS to move from a CED designation for new medical technologies to full coverage.
CMS’ move is just the latest example of cost-based thinking trumping patient-centric care
And, as per a recent article in BioCentury, there are significant unintended consequences that will impact the future of personalized medicine.
The cost of demonstrating clinical utility, along with the lack of clear or consistent standards, is killing a business model that had made it possible for small companies to commercialize molecular diagnostics quickly and cheaply. The fate of these laboratory-developed molecular diagnostics companies, and especially the conclusions investors draw about the viability of the space, could shape the future of personalized medicine.
According to research by the Tufts Center for the Study of Drug Development, without clinically useful diagnostics, personalized medicine growth will occur at a relatively slow pace.
And personalized medicine represents the future of healthcare around the world.
Let’s cut to the chase, if we are going to take meaningful strides both in addressing Alzheimer’s Disease specifically and in personalized medicine more broadly, we should not rely on Coverage with Evidence Development (CED) criteria in cases where the FDA’s approval process has expressly evaluated and endorsed the use of a drug or biologic in a specific patient population.
Fact: The evidence on amyloid imaging supports coverage for the population as identified by the Amyloid Imaging Task Force through Appropriate Use Criteria (AUC). A task force, convened by the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging, recommends coverage in this population based on a comprehensive review of the literature and expert consensus.
Fact: CMS currently covers similar PET technologies to aid in the diagnosis of Alzheimer’s Disease and other forms of cognitive decline. The agency has not previously required evidence of health outcome improvement as a condition of such coverage.
Fact: Using CED alone will deny Medicare beneficiaries adequate and rapid access to this technology, as the path to implementation is unclear. Such uncertainty in the reimbursement process strongly dis-incentivizes future investments in research and development. And without innovation there will not be advances in personalized medicine.
Wither “sustainable innovation?”
Why even bother with expedited review and similar FDA pathways? Clearly closer FDA/CMS coordination is required to address both the will of Congress – and the future of American healthcare.
In the absence of either an FY 2014 appropriation or a Continuing Resolution for FDA, beginning on October 1 and continuing until the date of enactment of an FY 2014 appropriation or Continuing Resolution ("lapse period"), agency operations will be limited to the following:
- Emergency work involving the safety of human life or the protection of property;
- Criminal law enforcement work; and
- Activities funded by carryover user fee balances, including user fee balances under the Prescription Drug User Fee Act (PDUFA), Generic Drug User Fee Amendments (GDUFA), Medical Device User Fee Amendments (MDUFA), Animal Drug User Fee Act (ADUFA), Animal Generic Drug User Fee Act (AGDUFA), and Family Smoking Prevention and Tobacco Control Act. Carryover user fee balances will only be spent on activities for which the fees are authorized under the Federal Food, Drug, and Cosmetic Act (FD&C Act).
With respect to medical product user fees, during the lapse period, FDA will not have legal authority to accept user fees assessed for FY 2014 until an FY 2014 appropriation for FDA is enacted. This will mean that FDA will not be able to accept any regulatory submissions for FY 2014 that require a fee payment and that are submitted during the lapse period.
If you’re following the multifaceted and global debate over biosimilars, Steve Usdin’s article, Biosimilar battlefronts, is a must read. Authored by BioCentury's Steve Usdin, it’s opening paragraphs set the tone,
Biosimilars developers, manufacturers of originator biologics, payers and consumer groups are battling in state capitals, at FDA headquarters, and at the World Health Organization in Geneva over the rules that will shape perceptions and prescribing practices for copycat biologics in the U.S. and around the world.
Separately, none of the conflicts will have a decisive effect on either biosimilars developers or manufacturers of the products they hope to replace. But collectively, state laws on interchangeable biosimilar substitution, national and international naming practices, and FDA's labeling policies could have powerful effects on the market penetration of biosimilars.
The article covers many issues, both foreign and domestic – and one of the most important and most contentious is the issue of the nonproprietary names assigned to biosimilar and interchangeable biologics.
Usdin writes,
Proponents of distinctive non-proprietary names, including some of the biggest biotech companies, say patient safety and possibly the viability of whole classes of biologic drugs would be threatened by a failure to adopt their recommendations.
However, European regulators say distinct non-proprietary names are unnecessary, and some biosimilars companies argue such a naming scheme would put a dark cloud over biosimilar products that would substantially reduce sales.
A WHO group will meet on Oct. 22 to debate biosimilars naming principles.
The basic disagreement: one camp is arguing for biosimilars to keep the same international non-proprietary name (INN) as the reference product; a second camp argues for distinct INNs.
Supporters of distinct INNs say the ability of regulators to track and trace biologic drugs is essential for patient safety and the commercial viability of biologics — original and biosimilar. Opponents of distinct INNs say they are intended to confuse and scare physicians, patients and payers by drawing unnecessary distinctions between original biologics and biosimilars.
According to Geoffrey Eich, executive director of R&D policy at Amgen, “It seems counterintuitive, like sticking your head in the sand, to not want to include a distinguishing feature that allows us to aggregate info when appropriate and disaggregate when appropriate.”
Amgen supports the use of the reference product’s root INN, with the addition of a unique suffix or prefix for each biosimilar. “We believe having some kind of a distinguishable feature is absolutely essential to patient welfare, for pharmacovigilance,” Amgen’s Eich told BioCentury.
A WHO working group will meet Oct. 22-24 to discuss the creation of voluntary international standards for non-proprietary names for biosimilars.
WHO isn’t likely to adopt a final naming policy at the October meeting. Whatever policy it eventually adopts will not be binding, but it is likely to be adopted by developing countries, and, if it includes a distinctive naming system, could intensify pressure on European countries to adopt new naming policies.
Without casting any aspersions, “quality” and “pharmacovigilance” in developing countries takes on an entirely different meaning than similar concepts in more developed regulatory regimes.
At a meeting in Pretoria last week Tomas Salmonson, Chair of the EMA’s Committee for Medicinal Products for Human Use (CHMP), said that the working group is “split down the middle” on the issue of naming.
Stay tuned.
We do what we must, and call it by the best names. -- Ralph Waldo Emerson
BioCentury This Week is must see TV – especially if you work in the FDA’s government affairs office.
On this weekend’s program Representative Dr. Mike Burgess (R, TX) said that the OMB misinterpreted the law – and that user fees shouldn't have been sequestered.
Dr. Burgess’ comments can be found here.
Dr. Charles Inturrisi is Professor of Pharmacology at Weill Cornell Medical College. He also has appointments in the Neuroscience Program at WCMC and with the Pain and Palliative Care Service, of the Memorial Sloan-Kettering Cancer Center and with the Drug Abuse Center at The Rockefeller University.
Dr. Inturrisi's current research is measuring the long term outcomes of treatments for chronic cancer and noncancer pain received by patients at four hospital-based outpatient Pain Clinics. He continues to have an interest the role of glutamate receptors in injury-induced pain and opioid tolerance, dependence and addictive behaviors. His research is directed at the discovery of new treatments for pain and drug addiction.
Dr. Inturrisi has received the John J. Bonica award of the Eastern Pain Association, a Distinguished Alumnus award from the University of Connecticut and the Excellence in Mentoring Award, Weill Cornell Medical College Postdoctoral Association. In 2008, Dr. Inturrisi received the first Graduate Dean’s Award for Excellence in Teaching and Mentoring of Graduate Students, presented by the Weill Cornell Graduate School of Medical Sciences.
He served as the president of the American Pain Society from 2008 to 2010 and in 2013 received the Distinguished Service Award from APS.
He was a member of the Institute of Medicine Committee that prepared the 2011 Report entitled “Relieving Pain in America”.
You can listen to Dr. Inturrisi’s presentation here (at the 1:03 mark) and the panel discussion that followed here.
Judy Foreman is a nationally syndicated health columnist whose “Health Sense” columns have appeared regularly in the Boston Globe, Los Angeles Times, Dallas Morning News and other national and international outlets. For years, she also wrote the Globe’s popular short feature, “Health Answers.”
She graduated Phi Beta Kappa from Wellesley College, served in the Peace Corps in Brazil for three years, then got a Master’s degree from the Harvard Graduate School of Education. From 2001 to 2004, she was a Lecturer on Medicine at Harvard Medical School and, for most of this time, was a scholar at the Brandeis Women’s Research Center. She has also been the host of a weekly, call-in radio show on Healthtalk.com and has won more than 50 journalism awards.
Her book on chronic pain, “A Nation in Pain – Healing Our Biggest Health Problem,” is due out in January, 2014 from Oxford University Press.
Steve Usdin has been Washington Editor of BioCentury since 1993, and has spent the past 20 years in the nation's capital covering political and policy issues affecting the life sciences sector. He also is the host of BioCentury This Week, BioCentury's weekly public affairs television program, as well as BioCentury Senior Editor responsible for coverage of social issues involving biotechnology. Steve’s reporting about biotechnology and biomedical policy has been cited in The Economist, The Wall Street Journal, the Washington Post, New Scientist and other publications. In 2012, the FDA Alumni Association named Steve the Harvey W. Wiley Lecturer, making him the first journalist to receive the Wiley Award. His book, “Engineering Communism: How Two Americans Spied for Stalin and Founded the Soviet Silicon Valley,” was published in 2005 by Yale University Press.
You can listen to Judy Foreman’s presentation and the panel discussion moderated by Peter Pitts here.
India's Protectionist Prescription
At the recent Group of 20 Summit, Indian Prime Minister Manmohan Singh implored American policymakers to recommit to encouraging robust growth in India and other emerging markets. It was a surprising request from a leader who has spent the past year overseeing a barrage of damaging reforms that threaten the American economy — and India’s prosperity.
India has been systematically shutting out foreign goods in an effort to prop up domestic industries. Indian officials have recklessly ignored basic intellectual-property protections, unfairly bolstering their own businesses at the expense of improved public health. America’s leaders need to make clear that a fair and open relationship benefits both India and the United States. If India wants to remain a valued economic partner, this kind of crude protectionism won’t be tolerated.
In recent months, India’s policymakers have pulled out all the stops to give homegrown companies an unfair advantage. Since the beginning of last year, the government has raised customs duties on high-end cars from 75 percent to 100 percent. In April, leaders mandated that all cosmetic products be registered with the Indian government prior to marketing there — a bureaucratic hurdle designed to obstruct foreign firms. Yet another new regulation requires that procurements by the country’s military give priority to Indian defense firms.
All together, the country has enacted 33 potentially trade-restricting measures since October 2008, according to a recent report from the European Commission. Where India’s self-serving policies have been especially irresponsible, however, is in the area of intellectual property, particularly for cutting-edge pharmaceuticals.
The country’s blatant disregard for intellectual-property rights was made clear in April, when India’s Supreme Court denied patent protection for a new form of the cancer drug Gleevec. In doing so, the court gave India’s $22 billion domestic drug industry free rein to sell copycat versions of the treatment. Indian officials were quick to declare the decision a victory for their poorest citizens, applauding the court for helping to make sophisticated medicines more affordable.
This claim, however, entirely misrepresents the decision and its consequences. Officials strategically neglected to mention that 95 percent of Indians who rely on Gleevec already receive the drug free of charge, thanks to a program supported by the drug’s manufacturer, Novartis. The Gleevec case was never about improving pharmaceutical access; the real intent was always to benefit India’s drug manufacturers.
By unfairly boosting the country’s generic industry, the court announced to health care research firms around the world that India is no friend to cutting-edge treatments — and the repercussions of such a message could be severe.
A breakthrough drug such as Gleevec requires, on average, more than a decade of trial and error to create and costs firms more than $1 billion. If India isn’t willing to protect the basic intellectual-property protections companies need to earn back some of that investment, drug firms won’t be able to offer their products to Indian patients, much less give them away for free. Considering India is home to the largest population of people who lack access to essential drugs, Indian leaders can ill afford to shun foreign pharmaceutical companies and the advanced medicines they offer.
Additionally, there is the direct threat India’s policies pose to the American economy. U.S. exports to India totaled $33 billion in 2011, an increase of more than 12 percent from the year before. As Rep. John B. Larson, Connecticut Democrat, and Rep. Erik Paulsen, Minnesota Republican, noted in a recent letter to fellow lawmakers in Congress, no fewer than 75 U.S. industries depend on intellectual-property protections. All told, companies in these fields are responsible for roughly 40 million American jobs.
America’s technology, agriculture and information-technology industries — among other sectors — are already feeling the effects of India’s current policies. If India continues to erect trade barriers, more and more U.S. firms will be denied a valuable and growing market for their goods.
What’s more, if our leaders don’t reverse this protectionist shift, many other nations may follow suit. In fact, many already have: The European Commission found that between May 2012 and May 2013, 154 new trade-restricting measures were adopted around the world, while only 18 were lifted.
As Mr. Singh made clear at the G-20 summit, America continues to have considerable influence on India’s economic future. It’s time our leaders use this clout to pressure India’s government to abandon their destructive trade policies. Officials in Washington must demonstrate to India — and the world — that fair economic partnerships are mutually beneficial and that protectionist tactics won’t be tolerated.
Peter J. Pitts, a former associate commissioner at the Food and Drug Administration, is president of the Center for Medicine in the Public Interest.
Another biologics nomenclature Citizen Petition was filed before this (see www.biopharmacopeia.com). The GPhA petition concerns the issue of established/official nonproprietary names (useable for marketing and prescription filling), particularly, whether these should be unique or not (generic). The earlier petition was filed in June by the Biotechnology Information Institute (R. Rader). It requests FDA assign both unofficial unique and biosimilar/(bio)generic-like (or class) names (and/or other identifiers) upon biologics approvals, along with public disclosures of needed basic agent/product descriptive information, including regarding supplemental approvals (product drift). These names (and the nomenclature system) need to be coherent science/entity/product-based, i.e., totally new and with no connection or carry-over from INN/USAN, which as a legacy pre-recombinant nomenclature system is simply not workable with modern biologics.
Thank you.
Ronald A. Rader
President
Biotechnology Information Institute
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
